Aminoalkylamino derivative of aromatic aminohydroxy or polyamino compounds



Patented May 6, 1930- UNITED STATES PATLENT- OFFICE WERNER SCHULEMANN,OF VOHWINKEL, AND WALTER KROPP, F ELBERFELD, GER- MANY, ASSIGNORS T0WINTHROP CHEMICAL COMPANY, INC., OF NEW YORK, N. Y.

AMINOALKYL AMINO DERIVATIVE OF ABOMA'I'IC AMINOHYDROXY OR POLYAMINOCOMPOUNDS No Drawing. Application filed June 30,1927, Serial No.202,741, and in Germany July 8, 1926.

The present invention relates to new aminoalkylamino derivatives ofaromatic aminohydroxyor polyamino compounds and more particularly to thecompounds of the general formula:

in which R designates. an aromatic radicle of the group including thebenzene and naphthalene series substituted by at least one amino-,alkylamino-, hydroxyor alkoxygroup, R stands for hydrogen, alkyl,alkylamino, alkylaminoalkyl or dialkylaminoalkyl, R stands for analkylene group, the carbon atom chain of which may be interrupted byoxygen, sulphur or nitrogen, or for the res idue 0t an isocyclic orheterocyclic compound,

X and X stand for alkyl groups one of which may be substituted byhydrogen, or

'for the carbon chain of a heterocyclic compound, in which case theoutermost N will be part of the ring.

These compounds can be obtained, for instance, by heating aromaticamino-hydroxyor polyamino-compounds of the benzene or naphthalene serieswith a halogen-alkylamino-dialkyl compound. In this process it isgenerally advantageous to add an acid- 30 binding agent and to use adiluent or a solvent.

Our new compounds are likewise obtainable by causing aromaticamino-hydroxyor polyamino-compounds of the benzene or naphthalene seriesto be acted upon by ethylene oxide ora halogenized alcohol and byconverting the hydroxyalkylamino derivatives thus obtained into thedialkylaminoalkyl compounds according to the usual methods. We do .notspecifically mention here all processes suitable for preparing ourcompounds, some other processes being described in the examples.

The following examples serve to illustrate our invention withoutlimiting it thereto, all parts being by weight.

Ewample 1.-A solution of 109 parts l-amino-3-hydroXy-benzene in 200 ccm.benzene are mixed with a solution of 140 parts diethyl- 50aminoethyl-chloride in 200 ccm. benzene anddroxy-l-diethylamino-ethyl-amino benzenedistills over as a viscous oil.

It has the formula:

By treatment with ether-hydrochloric acid its hygroscopical chlorinehydrate is obtained, which is easily soluble in water.

If, as starting material, 3-hydroxy-1-N- monoethyl-amino-benzene is usedand the process is carried out in the same way as described above, the3-hydroXy-1-N-(ethyl-)- diethy1-amino-ethylamino-benzene of the formula:

is obtained, which boils under a pressure of 2 mm. at a temperature of175 0., and has a melting point of C. It possesses similar properties ofthe compound described above.

Emam-ple 2.-110 parts of resorcine and 130 parts of asymetricalmethyl-diethylethylenediamine of the formula:

C2115 N-CIIr-CHr-N n CgHs are heated for several hours on the oil bathto a temperature of about 200 C. The reac tion mass is extracted withdiluted hydro chloric acid whereby the unchanged resor cine remainsundissolved. Then the hydrochloric acid solution is made alkaline andthe unchanged diamino-compouncls are extracted by ether. By acidifyingagain the alkaline solution, adding carbonate of potash and extractingby ether, the 1.-hydroxy-3-N- (methyl)-*diethyl-amino-ethylamino'benzene is Obtained which has, under apressure of 0.5 mm., a boiling point of 151 C., and has the formula:

HOQN CHa CHz-CHaNKCzHaYB Ewample 3. 16 parts3.4-diethoxy-1-aminobenzene, 14 parts diethylamino-ethylchloride and 0.5parts water are heated 2 hours to 8090 .0. Then water and soda lye areadded and the Whole is extracted with chloroform. The chloroformsolution is dried with sodium sulfate, the chloroform evaporated and theresidue purified by distillation in a vacuum. The reaction productdistils over under a pressure of 2 mm. at a temperature of 185-186 C. Ithas the formula:

oom-

and possesses excellent properties against blood parasites.

Example 4.25 parts l-diethylamino ethylamino-3.4-diethoxy-benzene,described in EX- ample 3, are heated together with parts d1-ethylamino-ethylchloride 5-6 hours to 130 140 C. The reaction mass isdiluted with water and soda lye and extracted with ether. The etherealsolution is dried, the ether evaporated and the residue purified bydistillation under a vacuum. At first some unchanged starting materialdistils over, then at a temperature of 203204 C., under a pressure of1.5 mm. the reaction product distils over. It

has the formula:

ooim

. 63 (3., and at a pressure of 3 mm. the boiling 65 pressure of 2.5mm.the new compound distilsfor 10 hours.

cnr-ommolmh Hr-CHJ.N( HI):

and possesses excellent properties against blood parasites. v Ewample5.21 parts 2.6-di-is'opropyloxyl-amino-benzene having the melting pointpoint 123 C. are heated to boiling under a reflux condenser togetherwith 28 parts diethylamino-ethylchloride and 30 parts water worked up asin theother examples. Under a The reaction mixture is.

over at a temperature of 188190 C., forming a colorless oil of thefollowing formula:

It forms a solid chlorine hydrate which is I OCH;

Ewaiuple '7.A solution of 100 parts 3- nitro-1-aminobenzene in 500 ccm.benzene is mixed with a solution of 98 parts diethylamino-ethylchloridein com. benzene and heated for several hours on the water bath. Aftercooling, the hydrochloric acid salt separates; it is filtered off,dissolved in water and reduced by means of iron and acetic acid. Thenthe solution is freed from iron, evaporated to a smallvolume, and afteraddition of potash, extracted with ether and worked up as usual. The1-amino-3 N-diethyl-aminoethylamino-benzene thus obtained boils under apressure of 1 mm. at a temperature of 158-159 C. It has the formula:

- NH: I

Example 8.--The N-(methyD-dieth'ylaniino-ethylaminobenzene obtained by.introducing one-diethylamino-ethyl group into mono- Infet-nylaminobenzene is converted into the p-nitroso compound bytreatment with sodium nitrite and hydrochloric acid while cooling well.The p-nitroso compound is then reduced by introducing zinc dust. "Alayer of ether is laid over the aqueous solution and while coolingconcentrated soda lye is added until the zinc hydroxide is completelydissolved. By working up as in the other examples the 4-amino-N-(methyl) -diethylaminoethylaminobenzene is obtained which boils under apressure of 3 mm. at a temperature of Mil-163 0., having the formula:

which boils under a pressure of 1 mm. at a temperature of 186 C.

Ewample 10.--15 parts of the zinc salt of thel-amino-4-dimethylamino-2-thiophenol are .dissolved in 17 5 parts ofwarm soda lye of 8% strength. The solution is filtered, 8 partsmethyliodide are added at a temperature of about 40-45 C. After thereaction is finished, the solution is extracted with ether.

- The residue which remains when evaporating the ether, is purified bydistillation. The l-amino -4 dimethylamino-2 -methylthiophen01 isobtained which boils under a pressure of 3 mm. ata temperature of 135C., forming an oily liquid.

6 parts of this compound are heated toget-her with 13.5 parts (about 3mol) diethylamino-ethylchloride and 6 parts benzene to a temperature ofabout 12013O C. After working up in the usual manner thel-didiethylaminoethylamino) 4- dimethylamino-2-methylthiophenol isobtained which boils under a pressure of 2 mm. at a temperature of198204 C. and forms a yellow oil. It has the formula:

SCH:

When treated with dry hydrochloric acid in ethereal solution, it forms awhite chlorine hydrate which is easily soluble in water.

Ewample 11.18 parts 3-methoxy-4-iso propyloxy-1-aminobenzene are heatedtogether wit-h 28 parts of the dichlorine hydrate of the (ethyl-) -di(ethyl-) amino (ethyl-) -a minoethylchlo'ride for 8 hours to 100-110 C.By working up in the usual manner the compound of the following formulais obtained:

which boils under a pressure of 2 mm. at a temperature of l89-191 (l,forming a colorless oil and a solid chlorine hydrate, easily soluble inwater.

In analogous manner are obtained, for instance, the following compounds:

3 methoxy -4-isopropyloxy-1- N (ozpiperidly ,8 hydroxy y -propyl)aminobenzene,

prepared by heating 3-methoxy-4-isopropyloxy-l-aminobenzene (m. p. 68-69(1), with epichlorhydrine and piperidine, boiling under a pressure of 5mm. at a temperature of 225- 230 and melting at 9294 (l, 3-n1ethoxy-4-isopropyloxy 1N- B-ethyl-,B-diethylaminoethylsulfide)-aminobenzene,prepared by treating 3-metho'xy-4-isopropyloxy-1-aminobenzene with (C H.N.CH .CH SCH CH Gl (hydro chloride), is a viscous oil, boiling under apressure of 5 mm. at a temperature of 225-227 C. i i

3 -n1ethoxy 4-isopropyloxy-1-N- (,8-ethyl- ,8 diethylamino et-hylether)aminobenzene boiling under a pressure of 1.5 mm. at a temperature of186188 C., is obtained by heating 3 methoxy 4isopropyloxy-l-aminobenzene with the hydrochloride of (C 11 .N.(JH ,()H.().(ll-L.CH Cl (boiling point 72-73 C. under 5 mm.).

3 methoxy 4 isopropyloxy 1- N (oz-(llmethylaminoy -ethoXy- 8 -propyl)-aminobenzene, boiling under a pressure of 1 mm. at a temperature of166-168 0., obtained by treating 3-methoxy-4-isopropyloxy-l-aminobenzenewith the hydrochloride of (CH NGH CH Cl) .OH .O.G H

(boiling point 6970 under 15 mm. pressure 3 methoxy 4 isopropyloxy 1 -N-(1'-dimethylamino-2'-cyelohexyl-) aminobenzene,

boiling under a pressure of 2 mm. at a temperature of 173175 0., formedby heating of 3- methoxy 4 isopropyloxy 1 aminobenzene with l-chloro 2dimethylamino-cyclohexane (boiling point 77-79 C. under 10 mm.pressure).

Example 12.-The sodium salt of 2.3-dihydroxynaphthalene- 1 azobenzenesulfonic acid are methylated with dimethyl sulfate in 1 .I

the usual manner and convertcd'by reduction with stannous chloride intothe 2.3 dimethoxy-l-amino-naphthalene which distils under a pressure of2 mm. at a temperature of 167 C.

2 parts of this compound are heated to-- gether with 8 parts benzene and.3 parts diethylamino-ethylchloride for 8 hours to a temperature ofabout 90 C. After cooling, the hydrochloride salt separates, is filteredby suction and decomposed with soda lye, The free base thus obtaineddistils under a pressure of 2 mm. at a temperature of 207 C., forming acolorless oil which is easily soluble in hydrochloric acid. It has theformula:

H cm-ommomm OCH:

Whenthis base is treated once more with diethylamino-ethylchloride, thecompound of the following formula is obtained:

OCH;

which boils under a pressure of 2 mm. at 240 C.

Example 13.The dry potassium salt of l-methoxy-2-hydroxy-5-nitrobenzeneis suspended in xylene and is caused to be acted upon by the equivalentamount of diethylamino-ethylchloride at a temperature of 135 C., wherebythe l-methoxy-2-diethylaminoethoxy-5-nitrobenzene is obtained whichiboils under a pressure of 2 mm. at a temperature of 187190 C. Byreduction by means of iron and acetic acid, the l-methoxy-2 diethylaminoethoxy 5 aminobenzene is obtained which boils under a pressure of 2 mm.at a temperature of 178180 C. It has the formula:

OCHr-C 2- a s)a This amine is dissolved in xylene and treated atatemperature of 120 (3., with the m.olecu-.

lar amount of diethylamino-ethylchloride. The separating salt isdissolved in water and decomposed by means of soda lye. The compoundthus obtained has the formula:

OHaO

' NH-onr-omNaJm:

It boils under a pressure of 2 mm. at a temperature of'218222 C.

, We claim:

1. As new products the aromatic com pounds of the general formula inwhich R designates an aromatic radicle of the group including thebenzene and naphthalene series substituted by at least one amino-,alkylamino-, hydroxyor alkoxy group, R stands forhydrogen, alkyl,alkylamino, alkylaminoalkyl or dialkylaminoalkyl, R stands for analkylene group, the carbon atom chain of which maybe interrupted byoxygen, sulphur ornitrogen, or for the residue of an isocyclic orheterocyclic compound, X and X stand for alkyl groups one of which maybesubstituted by hydrogen, or

for the carbon chain of a heterocycliccompound in which case theoutermost N will be part of the ring, which compounds are generallyviscous oils of a high boiling point and possess valuable pharmaceuticalpropertles,

especially a high efficiency against blood parasites.

2. As new products the aromatic compounds of the general formula:

in which R designates an aromatic radicle of the group including thebenzene and naphthalene series substituted by at least one amino-,alkylamino-, hydroxyor alkoxygroup, R stands for hydrogen, alkyl,alkylammo, alkylaminoalkyl or di-alkylami oin which R designates anaromatic radicle of the group including the benzene and naphthaleneseries substituted by at least one amino-, alkylamino-, hydroxyor alkoxgroup, R stands for hydrogen which may e substituted by a substituent ofthe group comprising alkylaminoalkyl and di-alk vlarninoalkyl, R standsfor an alkylene group,-X and X stand for alkyl groups one of whichpounds are generally viscous oils of a high boiling point and possessvaluable pharmaceutical properties, especially a high efficiency againstblood parasites.

may be substituted by hydrogen, which com- 4. As new products thearomatic compounds of the general formula:

wherein R stands for hydrogen, an alkyl-, or dialkylaminoalkyl group, Xstands for alkyl or dialkylaminoalkyl and Y stands for hydrogen, atleast one hydrogen atom being substituted by an amino-, alkylamino-hy-'droxyor alkoxy-group, which compounds are generally viscous oils of ahigh boiling point and possessing valuable pharmaceutical properties,especially a high efiiciency against blood parasites.

5. As new products the compounds of the following formula:

R YO N can wherein R stands for hydrogen or the group 02135 CHz.CHz.N

which are generally viscous oils of a high boiling point and possessvaluable pharmaceutical properties, especially a high efliciency againstblood parasites.

7. As a new product the compound of the formula:

CH on,.oH,.N 5 C2115 02350 N which is a viscous oil boiling under apressure of 1,5 mm. at a temperature of 203-204 O. and possessesvaluable pharmaceutical properties, especially a high efiiciency againstblood parasites.

In testimony whereof we have hereunto set our hands.

WERNER SGHULEMANN. WALTER KROPP.

